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Outcomes in Patients with Diabetic Macular Edema Requiring Cataract Surgery in VISTA and VIVID Studies
Journal Pre-proof Outcomes in Patients with Diabetic Macular Edema Requiring Cataract Surgery in VISTA and VIVID Studies Andrew A. Moshfeghi, MD, MBA, Desmond Thompson, PhD, Alyson J. Berliner, MD, Namrata Saroj, OD PII:
S2468-6530(19)30610-4
DOI:
https://doi.org/10.1016/j.oret.2019.10.015
Reference:
ORET 647
To appear in:
Ophthalmology Retina
Received Date: 3 July 2019 Revised Date:
25 October 2019
Accepted Date: 28 October 2019
Please cite this article as: Moshfeghi A.A., Thompson D., Berliner A.J. & Saroj N., Outcomes in Patients with Diabetic Macular Edema Requiring Cataract Surgery in VISTA and VIVID Studies, Ophthalmology Retina (2019), doi: https://doi.org/10.1016/j.oret.2019.10.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © YEAR Published by Elsevier Inc. on behalf of American Academy of Ophthalmology
1
Outcomes in Patients with Diabetic Macular Edema Requiring
2
Cataract Surgery in VISTA and VIVID Studies
3
Andrew A. Moshfeghi, MD, MBA,1 Desmond Thompson, PhD,2 Alyson J. Berliner, MD,2
4
Namrata Saroj, OD2
5
1
6
Keck School of Medicine, Los Angeles, California, United States
7
2
8
Meeting presentation: Presented, in part, at the 2016 Annual Meeting of the American
9
Academy of Ophthalmology (poster), Chicago, Illinois, United States; 2016 Annual Meeting of
10
The Retina Society, San Diego, California, United States; 2017 Angiogenesis, Exudation, and
11
Degeneration Annual Meeting, Bascom Palmer Eye Institute, Miami, Florida, United States; and
12
2017 Annual Meeting of the Association for Research in Vision and Ophthalmology in Baltimore,
13
Maryland, United States.
14
Financial support: This study was supported, in part, by an unrestricted grant to the
15
Department of Ophthalmology at the University of Southern California from Research to Prevent
16
Blindness, New York, New York, Unites States. The VISTA and VIVID studies were funded by
17
Regeneron Pharmaceuticals, Inc., Tarrytown, New York, United States, and Bayer HealthCare,
18
Berlin, Germany.
19
Conflict of interest: A.A.M. is a consultant for Allegro, Allergan, Alimera, Clearside, Bausch,
20
EyePoint, Novartis, Genentech, and Regeneron Pharmaceuticals, Inc.; served as a speaker for
21
Allergan; received research funding from Genentech and Regeneron Pharmaceuticals, Inc.; and
Department of Ophthalmology, University of Southern California Roski Eye Institute,
Regeneron Pharmaceuticals, Inc., Tarrytown, New York, United States.
1
22
holds equity interests in Pr3vent, OptiSTENT, and Visunex. D.T. is a consultant for Regeneron
23
Pharmaceuticals, Inc. A.J.B. is an employee of and stockholder in Regeneron Pharmaceuticals,
24
Inc. N.S. is a consultant for Aerie, Allegro, Apellis, Adverum, SamaCare, RegenexBio, and
25
Regeneron Pharmaceuticals, Inc. and an equity owner of Allegro, SamaCare, and Pr3vent.
26
Running head: Visual and anatomic outcomes in DME after IAI
27
Corresponding author:
28
Andrew A. Moshfeghi, MD, MBA
29
1450 San Pablo St., Suite 4700
30
USC Roski Eye Institute
31
Los Angeles, California 90033
32
United States
33
Phone: (323) 865-6933
34
Fax: (323) 442-6412
35
Email: [email protected]
36
Taxonomy topics: Edema, cataract surgery in diabetics, randomized clinical trial, vascular
37
endothelial growth factor, aflibercept
2
38
Abbreviations:
39
anti-VEGF = anti-vascular endothelial growth factor; BCVA = best-corrected visual acuity; CI =
40
confidence interval; CME = cystoid macular edema; CRT = central retinal thickness; DME =
41
diabetic macular edema; IAI = intravitreal aflibercept injection; OCT = optical coherence
42
tomography; PH = proportional hazards; q4 = every 4 weeks; q8 = every 8 weeks; RR = rate
43
ratio; SD-OCT = spectral domain optical coherence tomography.
3
44
PRÉCIS
45
Cataract surgery performed in eyes receiving intravitreal aflibercept therapy without need for
46
rescue therapy for diabetic macular edema resulted in visual acuity improvements, despite a
47
transient and mild increase in central retinal thickness.
48
4
49
ABSTRACT
50
Purpose: To evaluate the impact of cataract surgery on visual and anatomic outcomes in
51
patients with diabetic macular edema treated with intravitreal aflibercept injection (IAI) or laser
52
control and who did not require rescue therapy.
53
Design: Post hoc analysis of two phase 3 trials, VISTA and VIVID.
54
Participants: Fifty-four (laser, n = 11; IAI, n = 43) patients who underwent cataract surgery
55
during the study period.
56
Methods: In VISTA and VIVID, patients received IAI 2 mg q4 weeks (2q4), IAI 2 mg q8 weeks
57
following 5 monthly doses (2q8), or laser control through week 100. Starting at week 24, if
58
rescue treatment criteria were met, IAI patients received laser, and laser patients received IAI
59
2q8 (following 5 monthly doses). Patients who received rescue treatment before cataract
60
surgery were excluded.
61
Main Outcome Measures: Best-corrected visual acuity (BCVA) and central retinal thickness
62
(CRT) in the laser control and pooled IAI groups before and after cataract surgery.
63
Results: The cumulative incidence of cataract surgery did not depend on treatment group
64
assignment (rate ratio [95% confidence interval] = 1.517 [0.782, 2.944]; P = 0.2174). At the last
65
study visit before surgery, BCVA was 62.2 and 56.9 letters, and CRT was 342 µm and 301 µm
66
in the laser control and IAI groups, respectively. At the first study visit post-cataract surgery,
67
BCVA was significantly improved in both laser control and IAI groups to 73.5 (P = 0.010
68
compared with last visit before surgery) and 67.2 (P < 0.001 compared with last visit before
69
surgery) letters, respectively. Corresponding change in CRT was a modest increase to 364 µm
70
(P > 0.05 compared with last visit before surgery) and 359 µm (P = 0.013 compared with last
71
visit before surgery), respectively.
72
Conclusions: Incidence of cataract surgery was similar in both treatment groups. Despite a
73
modest worsening in CRT after cataract surgery, BCVA was improved in both treatment groups.
5
74
Non-diabetic patients who undergo routine, uncomplicated cataract surgery with intraocular lens
75
implantation are at risk for developing cystoid macular edema (CME) in approximately 1% to 7%
76
of patients.1 Patients with existing diabetic macular edema (DME) are known to have an inner
77
blood retinal barrier with weaker integrity than non-diabetic patients, resulting in intraretinal
78
hemorrhages, retinal exudates, and macular edema.2 Cataract surgery, even in its modern
79
micro-incisional form, is still an invasive intraocular procedure that is associated with the
80
predictable release of pro-inflammatory cytokines.3 It is, therefore, not surprising that patients
81
with existing diabetic retinopathy who undergo cataract surgery are frequently found to either
82
develop new macular edema or to have an exacerbation of existing DME following the
83
procedure.4
84
Anti-vascular endothelial growth factor (anti-VEGF) agents like aflibercept can inhibit the
85
breakdown of the inner blood retinal barrier, thereby controlling and reversing DME with
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concomitant improvements in visual acuity.5 It has been previously shown in a post hoc analysis
87
of a prospective, randomized clinical trial that patients receiving ranibizumab therapy in phase 3
88
clinical trials of DME experienced a mean gain of approximately 2 lines of vision from the last
89
study visit before cataract surgery to the first study visit following cataract surgery.6 In that study,
90
however, robust optical coherence tomography (OCT) scans were not scheduled to be
91
performed at frequent enough intervals to evaluate whether there was an anatomic alteration of
92
the macula in the immediate post-operative period. While there was a demonstrated benefit with
93
respect to visual acuity, questions remained regarding the status of the macula in patients with
94
DME who undergo cataract surgery. Does the DME worsen following cataract surgery in the
95
patient undergoing intravitreal anti-VEGF therapy? If so, to what extent and for how long?
96
Coupled with these unanswered questions is the lack of data-driven guidance on how
97
physicians should manage patients with progressive, visually significant cataracts in the setting
98
of DME being managed by intravitreal anti-VEGF therapy. The goal of the present post hoc
99
analysis of the pivotal phase 3 registration trials of patients receiving intravitreal aflibercept 6
100
therapy for DME — VIVID and VISTA5,7 — was to characterize patients' visual and anatomic
101
outcomes following cataract surgical intervention.
7
102
Methods
103
VISTA and VIVID Study Design
104
VISTA and VIVID were two similarly designed, double-masked, randomized, active-controlled,
105
phase 3 trials, which randomized 872 patients. VISTA (registered at www.clinicaltrials.gov;
106
NCT01363440) was conducted across 54 sites in the United States, and VIVID (registered at
107
www.clinicaltrials.gov; NCT01331681) was conducted at 73 sites across Australia, Europe, and
108
Japan. Each clinical site’s respective institutional review board/ethics committee approved the
109
study. All patients provided written informed consent. Both studies were carried out in
110
compliance with ethical guidelines of the Declaration of Helsinki and the Health Insurance
111
Portability and Accountability Act. The study design and patient eligibility for the VISTA and
112
VIVID trials have previously been described.5,7
113
Eyes were randomized in a 1:1:1 ratio to receive either 2 mg intravitreal aflibercept
114
injection (IAI) every 4 weeks (2q4), 2 mg IAI every 8 weeks after 5 initial monthly doses with
115
sham injections on non-treatment visits (2q8), or macular laser photocoagulation at baseline
116
and at visits in which patients met any of the laser retreatment criteria (laser control). Beginning
117
at week 12, if the laser retreatment criteria were met, study eyes in the 2q4 and 2q8 groups
118
received sham laser and those in the laser control group received active laser, but not more
119
frequently than every 12 weeks. Beginning at week 24, when the pre-specified additional
120
(rescue) treatment criteria were met, study eyes in the 2q4 and 2q8 groups received active
121
laser, while those in the laser control group received 5 doses of 2 mg IAI every 4 weeks
122
followed by dosing every 8 weeks.5,7
8
123
Study Population
124
Patients who underwent cataract surgery in the study eye during the study follow-up period
125
through week 100 were included. Need for cataract surgery was at the investigator’s discretion.
126
There was no protocol-mandated period between cataract surgery and study treatment.
127
Patients with prior history of cataract surgery, as determined by investigator-reported
128
medical history and baseline clinical examination, were excluded. Occurrence of cataract
129
surgery during the study was based on investigator-reported concurrent ocular procedures
130
during the study follow-up through week 100. Patients who received rescue treatment prior to
131
cataract surgery were excluded from the analysis. Patients who received rescue treatment
132
following cataract surgery were censored at the time of rescue treatment.
133
Outcome Measures
134
This post hoc analysis of randomized clinical trial data evaluated the effect of cataract surgery
135
on visual and anatomic outcomes in patients treated with IAI or laser for DME. Mean change in
136
best-corrected visual acuity (BCVA) and central retinal thickness (CRT), as measured by
137
spectral domain OCT (SD-OCT), before and after cataract surgery were examined.
138
Statistical Analyses
139
Data from both the VISTA and VIVID studies were integrated, as the outcomes across studies
140
were consistent, and the two IAI groups were combined. Eight hundred and sixty-two patients
141
who had baseline and at least one post-baseline BCVA measurement were assessed (laser
142
control, n = 286 and IAI, n = 576). Of these patients, 579 patients with confirmed medical history
143
of no cataract surgery prior to study enrollment were assessed to determine if they underwent
144
cataract surgery (laser control, n = 197 and IAI, n = 382) during the study follow-up period
145
through week 100.
9
146
Time to an event and cumulative incidence was evaluated by Kaplan–Meier analysis.
147
The rate ratio (RR) comparing the IAI groups with the laser control group was estimated by the
148
Cox proportional hazards (PH) analysis. The relative hazard was determined as the ratio of the
149
rate in the laser control group to that in the IAI groups. The paired t test was used to evaluate
150
the difference in BCVA and CRT outcomes before and after surgery.
151 152
Observed data at each time point were included. All analyses described herein were post hoc and carried out in an exploratory manner.
10
153
Results
154
Cataract surgery was performed in the study eye of 20 (10.2%) patients in the laser control
155
group and 48 (12.6%) patients in the lAI group. The corresponding number of patients after
156
excluding those who received rescue therapy prior to cataract surgery were 11 (5.6%) and 43
157
eyes (11.3%), respectively. No patients received rescue therapy during the reported follow-up
158
period after cataract surgery.
159
The cumulative incidence of cataract surgery did not depend on treatment group
160
assignment (RR [95% confidence interval (CI)] = 1.517 [0.782, 2.944]; P = 0.2174). The
161
incidence of and time to cataract surgery were the same in the laser control and IAI groups (Fig
162
1).
163
Visual Acuity Outcomes
164
Patients undergoing cataract surgery had a baseline BCVA of 61.7 and 58.8 letters in the laser
165
control and IAI groups, respectively (Fig 2A). The corresponding BCVA at the last study visit
166
before surgery was 62.2 and 56.9 letters, respectively (Fig 2A). At the first study visit
167
post-cataract surgery, BCVA was significantly improved in both laser control and IAI groups to
168
73.5 (difference = 11.3 [95% CI: 3.4, 19.1]; P = 0.010 compared with last visit before surgery)
169
and 67.2 (difference = 10.7 [95% CI: 5.3, 16.0]; P < 0.001 compared with last visit before
170
surgery) letters, respectively. By the sixth study visit post-cataract surgery, BCVA had stabilized
171
to 68.8 (difference = 13.3 [95% CI: –13.9, 40.4]; P = 0.218 compared with last visit before
172
surgery) and 73.4 (difference = 15.6 [95% CI: 8.5, 22.7]; P < 0.001 compared with last visit
173
before surgery) letters in the laser control and IAI groups, respectively (Fig 2A). In the laser
174
control group, the lack of statistical significance for BCVA increase from the last visit before
175
surgery at the sixth study visit post-cataract surgery may be attributable to the small number of
176
patients in this group. 11
177
Overall, 0% and 7.0% of the patients in the laser control and IAI groups, respectively,
178
had gained ≥15 letters from baseline at the last study visit before cataract surgery. Following
179
cataract surgery, the cumulative incidence for patients who gained ≥15 letters were 35.1% and
180
46.6%, respectively (Fig 2B).
181
Anatomic Outcomes
182
Patients undergoing cataract surgery had a baseline CRT of 441 µm and 486 µm in the laser
183
control and IAI groups, respectively (Fig 3A). The corresponding CRT at the last study visit
184
before surgery was 342 µm and 301 µm, respectively. At the first study visit post-cataract
185
surgery, CRT increased in both groups to 364 µm (difference = 22.5 [95% CI: –22.5, 67.4]; P >
186
0.05 compared with last visit before surgery) and 359 µm (difference = 58.0 [95% CI: 13.2,
187
102.8]; P = 0.013 compared with last visit before surgery), respectively. By the sixth study visit
188
post-cataract surgery, CRT had stabilized to 430 µm (difference = 43.3 [95% CI: –71.3, 157.8];
189
P > 0.05 compared with last visit before surgery) and 360 µm (difference = 49.4 [95% CI: 5.1,
190
93.7]; P = 0.030 compared with last visit before surgery) in the laser control and IAI groups,
191
respectively (Fig 3A).
192
Overall, 45.5% and 58.1% of the patients in the laser control and IAI groups,
193
respectively, had CRT ≤300 µm on SD-OCT at the last study visit before cataract surgery.
194
Subsequently, at the first study visit after cataract surgery, the corresponding cumulative
195
incidence for patients with CRT ≤300 µm on SD-OCT were 27.3% and 46.2%, respectively (Fig
196
3B).
12
197
Discussion
198
This post hoc study revealed that the incidence of cataract surgery did not appear to be
199
dependent on treatment group assignment. This finding lends further credence to the notion that
200
intravitreal anti-VEGF therapy does not appear to hasten the development of cataracts
201
secondary to treatment with intravitreal corticosteroids.
202
In patients treated with IAI without any need for rescue treatment with laser and who
203
underwent cataract surgery, there was no observed change in BCVA from baseline to the last
204
visit before cataract surgery despite achieving normalization of the retina (mean CRT, 301 µm),
205
raising the possibility that the lack of BCVA improvement was due to the presence of worsening
206
cataracts. While it is possible the lack of vision improvement could have been due to irreversible
207
damage to the macula from chronic DME or macular ischemia, it should be noted that, on
208
average, patients still experienced an approximate 2-line gain in BCVA following cataract
209
surgery. Therefore, it is likely that the cataract was masking vision gains, which were then
210
revealed after the cataract was addressed surgically. Furthermore, with continued IAI treatment
211
and resultant control of the DME, the initial visual gains post-cataract surgery continued to
212
increase, finally stabilizing at approximately the sixth follow-up visit.
213
In contrast, while patients in the laser control group without need for rescue treatment
214
with IAI also had substantial visual acuity gains as a result of cataract surgery, the initial visual
215
gains started to decline around the third study visit post-cataract surgery. A corresponding
216
pattern was also seen for the change in CRT over time. This suggests that the visual gains
217
achieved following cataract extraction may be compromised without adequate treatment of for
218
DME. It should be noted, however, this trend was observed in a relatively small group of
219
patients (n = 11) in the analysis, and this exploratory finding should be considered in that
220
context.
13
221
These data support results from a post hoc analysis of the ranibizumab RISE and RIDE
222
studies, which used similar methodology as the present investigation. In that analysis,
223
Moshfeghi et al demonstrated a similar rate of cataract development and time to cataract
224
surgery across active treatment and control groups.6 Additionally, like the present study,
225
patients gained an average of 2 lines of vision from the last study visit before cataract surgery to
226
the first study visit following cataract surgery. This was true of study drug- and control-treated
227
eyes.6 That post hoc analysis differed from the present study insofar as only time-domain OCT
228
data were available from the RISE and RIDE studies, and the frequency of OCT assessments
229
precluded it from being a meaningful metric for post hoc analysis, especially in the second year.
230
Nevertheless, the consistency in the average visual acuity gain following cataract surgery using
231
a similar in-class agent for the same disease lends support to the findings here.
232
A strength of this sub-analysis is that the data derived from two large, prospective,
233
active-controlled, randomized, phase 3 clinical trials.5,7 Furthermore, in the IAI groups, a fixed
234
dosing algorithm was applied, which leads to a clearer interpretation of the data vis a vis the
235
timing of cataract surgery intervention. The necessity for, and timing of, cataract surgery was left
236
solely to investigator discretion, which is thus more reflective of the real-world clinical practice
237
setting. One major limitation is that this was a post hoc analysis in a relatively small number of
238
patients who required cataract surgery during the 2-year follow-up period. An additional
239
limitation is the relatively short follow-up period post-cataract surgery, as many of the cataract
240
surgeries were performed in the second year of the study. Because of the relatively rigid dosing
241
algorithms and variability in timing of cataract surgery due to investigator discretion, we are
242
unable to draw meaningful conclusions about the optimal time between an intravitreal anti-
243
VEGF injection and cataract surgery. In some respects, this limitation can be viewed as a
244
strength, since independent decisions by physicians in a real-world practice setting may be
245
similarly free of stringent guidance about the timing of cataract surgery. The fact that there were
246
no negative findings and that patients, on average, gained vision despite an initial transient and 14
247
modest increase in CRT should reassure physicians (e.g., retinal specialists, cataract surgeons)
248
and patients that proceeding with cataract surgery in the setting of actively treated DME is a
249
reasonable approach.8
250
In conclusion, we observed a similar incidence of cataract surgery for patients in both
251
the active treatment and laser control groups. Furthermore, no detrimental effect of cataract
252
surgery intervention was found in patients undergoing intravitreal anti-VEGF therapy in this post
253
hoc analysis. Rather, following cataract surgery, improved visual acuity was observed despite
254
an initial transient and modest increase in macular edema, as measured by SD-OCT imaging.
15
255
Acknowledgments
256
Medical writing support was provided by Saba Choudhary, PhD, of Prime Global, New York,
257
USA, according to Good Publication Practice guidelines (Link) and funded by Regeneron
258
Pharmaceuticals, Inc. All authors had full access to all the data in this study and take complete
259
responsibility for the integrity of the data and accuracy of the data analysis.
260
Author Contributions:
261
Conception and design: Moshfeghi, Thompson, Berliner, Saroj
262
Data acquisition and research execution: Moshfeghi, Thompson, Berliner, Saroj
263
Data analysis and interpretation: Moshfeghi, Thompson, Berliner, Saroj
264
Manuscript preparation and approval: Moshfeghi, Thompson, Berliner, Saroj
16
265
References
266
1.
Heier JS, Topping TM, Baumann W, et al. Ketorolac versus prednisolone versus
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combination therapy in the treatment of acute pseudophakic cystoid macular edema.
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Ophthalmology. 2000;107:2034-8;discussion 9.
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2.
Hartnett ME, Tinkham N, Paynter L, et al. Aqueous vascular endothelial growth factor as
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a predictor of macular thickening following cataract surgery in patients with diabetes
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mellitus. Am J Ophthalmol. 2009;148:895-901 e1.
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3.
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cataract surgery. Br J Ophthalmol. 1992;76:453-6. 4.
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Patel JI, Hykin PG, Cree IA. Diabetic cataract removal: postoperative progression of maculopathy--growth factor and clinical analysis. Br J Ophthalmol. 2006;90:697-701.
5.
277 278
Ferguson VM, Spalton DJ. Continued breakdown of the blood aqueous barrier following
Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121:2247-54.
6.
Moshfeghi AA, Shapiro H, Lemmon LA, Gune S. Impact of cataract surgery during
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treatment with ranibizumab in patients with diabetic macular edema. Ophthalmology
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Retina. 2018;2:86-90.
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7.
Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal aflibercept for diabetic macular
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edema: 100-week results from the VISTA and VIVID studies. Ophthalmology.
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2015;122:2044-52.
284 285
8.
Steinle NC, Lampen SIR, Wykoff CC. The intersection of diabetes mellitus and cataract surgery: current state of management. Ophthalmology Retina. 2018;2:83-5.
17
286
Figure 1. Kaplan–Meier Analysis Demonstrating Time to First Cataract Surgery in Patients
287
Receiving Intravitreal Aflibercept Injection (IAI) or Laser Control.
288 289
CI = confidence interval.
18
290
Figure 2. Visual Outcomes Following Cataract Surgery in Patients Receiving Intravitreal
291
Aflibercept Injection (IAI) or Laser Control. (A) Line graph representing best-corrected visual
292
acuity (BCVA) over time. aP = 0.010, bP < 0.001, and cP = 0.218 compared with last visit before
293
surgery. (B) Time to first sustained gain of ≥15 letters from the last visit before surgery.
294
ETDRS = Early Treatment Diabetic Retinopathy Study.
295 296
19
297
Figure 3. Anatomic Outcomes Following Cataract Surgery in Patients Receiving Intravitreal
298
Aflibercept Injection (IAI) or Laser Control. (A) Line graph representing optical coherence
299
tomography (OCT) central retinal thickness (CRT) over time. aP > 0.05, bP = 0.013, and cP =
300
0.030 compared with last visit before surgery. (B) Kaplan–Meier analysis of the time to first
301
sustained (observed at 2 consecutive visits) CRT ≤300 µm on spectral domain-optical
302
coherence tomography (SD-OCT) following cataract surgery in patients receiving IAI or laser
303
control.
304 305
20
PRÉCIS Cataract surgery performed in eyes receiving intravitreal aflibercept therapy without need for rescue therapy for diabetic macular edema resulted in visual acuity improvements, despite a transient and mild increase in central retinal thickness.
S2468-6530(19)30610-4
DOI:
https://doi.org/10.1016/j.oret.2019.10.015
Reference:
ORET 647
To appear in:
Ophthalmology Retina
Received Date: 3 July 2019 Revised Date:
25 October 2019
Accepted Date: 28 October 2019
Please cite this article as: Moshfeghi A.A., Thompson D., Berliner A.J. & Saroj N., Outcomes in Patients with Diabetic Macular Edema Requiring Cataract Surgery in VISTA and VIVID Studies, Ophthalmology Retina (2019), doi: https://doi.org/10.1016/j.oret.2019.10.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © YEAR Published by Elsevier Inc. on behalf of American Academy of Ophthalmology
1
Outcomes in Patients with Diabetic Macular Edema Requiring
2
Cataract Surgery in VISTA and VIVID Studies
3
Andrew A. Moshfeghi, MD, MBA,1 Desmond Thompson, PhD,2 Alyson J. Berliner, MD,2
4
Namrata Saroj, OD2
5
1
6
Keck School of Medicine, Los Angeles, California, United States
7
2
8
Meeting presentation: Presented, in part, at the 2016 Annual Meeting of the American
9
Academy of Ophthalmology (poster), Chicago, Illinois, United States; 2016 Annual Meeting of
10
The Retina Society, San Diego, California, United States; 2017 Angiogenesis, Exudation, and
11
Degeneration Annual Meeting, Bascom Palmer Eye Institute, Miami, Florida, United States; and
12
2017 Annual Meeting of the Association for Research in Vision and Ophthalmology in Baltimore,
13
Maryland, United States.
14
Financial support: This study was supported, in part, by an unrestricted grant to the
15
Department of Ophthalmology at the University of Southern California from Research to Prevent
16
Blindness, New York, New York, Unites States. The VISTA and VIVID studies were funded by
17
Regeneron Pharmaceuticals, Inc., Tarrytown, New York, United States, and Bayer HealthCare,
18
Berlin, Germany.
19
Conflict of interest: A.A.M. is a consultant for Allegro, Allergan, Alimera, Clearside, Bausch,
20
EyePoint, Novartis, Genentech, and Regeneron Pharmaceuticals, Inc.; served as a speaker for
21
Allergan; received research funding from Genentech and Regeneron Pharmaceuticals, Inc.; and
Department of Ophthalmology, University of Southern California Roski Eye Institute,
Regeneron Pharmaceuticals, Inc., Tarrytown, New York, United States.
1
22
holds equity interests in Pr3vent, OptiSTENT, and Visunex. D.T. is a consultant for Regeneron
23
Pharmaceuticals, Inc. A.J.B. is an employee of and stockholder in Regeneron Pharmaceuticals,
24
Inc. N.S. is a consultant for Aerie, Allegro, Apellis, Adverum, SamaCare, RegenexBio, and
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Regeneron Pharmaceuticals, Inc. and an equity owner of Allegro, SamaCare, and Pr3vent.
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Running head: Visual and anatomic outcomes in DME after IAI
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Corresponding author:
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Andrew A. Moshfeghi, MD, MBA
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1450 San Pablo St., Suite 4700
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USC Roski Eye Institute
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Los Angeles, California 90033
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United States
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Phone: (323) 865-6933
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Fax: (323) 442-6412
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Email: [email protected]
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Taxonomy topics: Edema, cataract surgery in diabetics, randomized clinical trial, vascular
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endothelial growth factor, aflibercept
2
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Abbreviations:
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anti-VEGF = anti-vascular endothelial growth factor; BCVA = best-corrected visual acuity; CI =
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confidence interval; CME = cystoid macular edema; CRT = central retinal thickness; DME =
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diabetic macular edema; IAI = intravitreal aflibercept injection; OCT = optical coherence
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tomography; PH = proportional hazards; q4 = every 4 weeks; q8 = every 8 weeks; RR = rate
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ratio; SD-OCT = spectral domain optical coherence tomography.
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PRÉCIS
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Cataract surgery performed in eyes receiving intravitreal aflibercept therapy without need for
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rescue therapy for diabetic macular edema resulted in visual acuity improvements, despite a
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transient and mild increase in central retinal thickness.
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4
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ABSTRACT
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Purpose: To evaluate the impact of cataract surgery on visual and anatomic outcomes in
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patients with diabetic macular edema treated with intravitreal aflibercept injection (IAI) or laser
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control and who did not require rescue therapy.
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Design: Post hoc analysis of two phase 3 trials, VISTA and VIVID.
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Participants: Fifty-four (laser, n = 11; IAI, n = 43) patients who underwent cataract surgery
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during the study period.
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Methods: In VISTA and VIVID, patients received IAI 2 mg q4 weeks (2q4), IAI 2 mg q8 weeks
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following 5 monthly doses (2q8), or laser control through week 100. Starting at week 24, if
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rescue treatment criteria were met, IAI patients received laser, and laser patients received IAI
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2q8 (following 5 monthly doses). Patients who received rescue treatment before cataract
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surgery were excluded.
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Main Outcome Measures: Best-corrected visual acuity (BCVA) and central retinal thickness
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(CRT) in the laser control and pooled IAI groups before and after cataract surgery.
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Results: The cumulative incidence of cataract surgery did not depend on treatment group
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assignment (rate ratio [95% confidence interval] = 1.517 [0.782, 2.944]; P = 0.2174). At the last
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study visit before surgery, BCVA was 62.2 and 56.9 letters, and CRT was 342 µm and 301 µm
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in the laser control and IAI groups, respectively. At the first study visit post-cataract surgery,
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BCVA was significantly improved in both laser control and IAI groups to 73.5 (P = 0.010
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compared with last visit before surgery) and 67.2 (P < 0.001 compared with last visit before
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surgery) letters, respectively. Corresponding change in CRT was a modest increase to 364 µm
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(P > 0.05 compared with last visit before surgery) and 359 µm (P = 0.013 compared with last
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visit before surgery), respectively.
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Conclusions: Incidence of cataract surgery was similar in both treatment groups. Despite a
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modest worsening in CRT after cataract surgery, BCVA was improved in both treatment groups.
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Non-diabetic patients who undergo routine, uncomplicated cataract surgery with intraocular lens
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implantation are at risk for developing cystoid macular edema (CME) in approximately 1% to 7%
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of patients.1 Patients with existing diabetic macular edema (DME) are known to have an inner
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blood retinal barrier with weaker integrity than non-diabetic patients, resulting in intraretinal
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hemorrhages, retinal exudates, and macular edema.2 Cataract surgery, even in its modern
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micro-incisional form, is still an invasive intraocular procedure that is associated with the
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predictable release of pro-inflammatory cytokines.3 It is, therefore, not surprising that patients
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with existing diabetic retinopathy who undergo cataract surgery are frequently found to either
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develop new macular edema or to have an exacerbation of existing DME following the
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procedure.4
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Anti-vascular endothelial growth factor (anti-VEGF) agents like aflibercept can inhibit the
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breakdown of the inner blood retinal barrier, thereby controlling and reversing DME with
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concomitant improvements in visual acuity.5 It has been previously shown in a post hoc analysis
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of a prospective, randomized clinical trial that patients receiving ranibizumab therapy in phase 3
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clinical trials of DME experienced a mean gain of approximately 2 lines of vision from the last
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study visit before cataract surgery to the first study visit following cataract surgery.6 In that study,
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however, robust optical coherence tomography (OCT) scans were not scheduled to be
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performed at frequent enough intervals to evaluate whether there was an anatomic alteration of
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the macula in the immediate post-operative period. While there was a demonstrated benefit with
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respect to visual acuity, questions remained regarding the status of the macula in patients with
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DME who undergo cataract surgery. Does the DME worsen following cataract surgery in the
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patient undergoing intravitreal anti-VEGF therapy? If so, to what extent and for how long?
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Coupled with these unanswered questions is the lack of data-driven guidance on how
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physicians should manage patients with progressive, visually significant cataracts in the setting
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of DME being managed by intravitreal anti-VEGF therapy. The goal of the present post hoc
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analysis of the pivotal phase 3 registration trials of patients receiving intravitreal aflibercept 6
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therapy for DME — VIVID and VISTA5,7 — was to characterize patients' visual and anatomic
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outcomes following cataract surgical intervention.
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Methods
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VISTA and VIVID Study Design
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VISTA and VIVID were two similarly designed, double-masked, randomized, active-controlled,
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phase 3 trials, which randomized 872 patients. VISTA (registered at www.clinicaltrials.gov;
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NCT01363440) was conducted across 54 sites in the United States, and VIVID (registered at
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www.clinicaltrials.gov; NCT01331681) was conducted at 73 sites across Australia, Europe, and
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Japan. Each clinical site’s respective institutional review board/ethics committee approved the
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study. All patients provided written informed consent. Both studies were carried out in
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compliance with ethical guidelines of the Declaration of Helsinki and the Health Insurance
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Portability and Accountability Act. The study design and patient eligibility for the VISTA and
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VIVID trials have previously been described.5,7
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Eyes were randomized in a 1:1:1 ratio to receive either 2 mg intravitreal aflibercept
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injection (IAI) every 4 weeks (2q4), 2 mg IAI every 8 weeks after 5 initial monthly doses with
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sham injections on non-treatment visits (2q8), or macular laser photocoagulation at baseline
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and at visits in which patients met any of the laser retreatment criteria (laser control). Beginning
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at week 12, if the laser retreatment criteria were met, study eyes in the 2q4 and 2q8 groups
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received sham laser and those in the laser control group received active laser, but not more
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frequently than every 12 weeks. Beginning at week 24, when the pre-specified additional
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(rescue) treatment criteria were met, study eyes in the 2q4 and 2q8 groups received active
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laser, while those in the laser control group received 5 doses of 2 mg IAI every 4 weeks
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followed by dosing every 8 weeks.5,7
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Study Population
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Patients who underwent cataract surgery in the study eye during the study follow-up period
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through week 100 were included. Need for cataract surgery was at the investigator’s discretion.
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There was no protocol-mandated period between cataract surgery and study treatment.
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Patients with prior history of cataract surgery, as determined by investigator-reported
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medical history and baseline clinical examination, were excluded. Occurrence of cataract
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surgery during the study was based on investigator-reported concurrent ocular procedures
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during the study follow-up through week 100. Patients who received rescue treatment prior to
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cataract surgery were excluded from the analysis. Patients who received rescue treatment
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following cataract surgery were censored at the time of rescue treatment.
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Outcome Measures
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This post hoc analysis of randomized clinical trial data evaluated the effect of cataract surgery
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on visual and anatomic outcomes in patients treated with IAI or laser for DME. Mean change in
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best-corrected visual acuity (BCVA) and central retinal thickness (CRT), as measured by
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spectral domain OCT (SD-OCT), before and after cataract surgery were examined.
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Statistical Analyses
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Data from both the VISTA and VIVID studies were integrated, as the outcomes across studies
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were consistent, and the two IAI groups were combined. Eight hundred and sixty-two patients
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who had baseline and at least one post-baseline BCVA measurement were assessed (laser
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control, n = 286 and IAI, n = 576). Of these patients, 579 patients with confirmed medical history
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of no cataract surgery prior to study enrollment were assessed to determine if they underwent
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cataract surgery (laser control, n = 197 and IAI, n = 382) during the study follow-up period
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through week 100.
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Time to an event and cumulative incidence was evaluated by Kaplan–Meier analysis.
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The rate ratio (RR) comparing the IAI groups with the laser control group was estimated by the
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Cox proportional hazards (PH) analysis. The relative hazard was determined as the ratio of the
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rate in the laser control group to that in the IAI groups. The paired t test was used to evaluate
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the difference in BCVA and CRT outcomes before and after surgery.
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Observed data at each time point were included. All analyses described herein were post hoc and carried out in an exploratory manner.
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Results
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Cataract surgery was performed in the study eye of 20 (10.2%) patients in the laser control
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group and 48 (12.6%) patients in the lAI group. The corresponding number of patients after
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excluding those who received rescue therapy prior to cataract surgery were 11 (5.6%) and 43
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eyes (11.3%), respectively. No patients received rescue therapy during the reported follow-up
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period after cataract surgery.
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The cumulative incidence of cataract surgery did not depend on treatment group
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assignment (RR [95% confidence interval (CI)] = 1.517 [0.782, 2.944]; P = 0.2174). The
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incidence of and time to cataract surgery were the same in the laser control and IAI groups (Fig
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1).
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Visual Acuity Outcomes
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Patients undergoing cataract surgery had a baseline BCVA of 61.7 and 58.8 letters in the laser
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control and IAI groups, respectively (Fig 2A). The corresponding BCVA at the last study visit
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before surgery was 62.2 and 56.9 letters, respectively (Fig 2A). At the first study visit
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post-cataract surgery, BCVA was significantly improved in both laser control and IAI groups to
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73.5 (difference = 11.3 [95% CI: 3.4, 19.1]; P = 0.010 compared with last visit before surgery)
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and 67.2 (difference = 10.7 [95% CI: 5.3, 16.0]; P < 0.001 compared with last visit before
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surgery) letters, respectively. By the sixth study visit post-cataract surgery, BCVA had stabilized
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to 68.8 (difference = 13.3 [95% CI: –13.9, 40.4]; P = 0.218 compared with last visit before
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surgery) and 73.4 (difference = 15.6 [95% CI: 8.5, 22.7]; P < 0.001 compared with last visit
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before surgery) letters in the laser control and IAI groups, respectively (Fig 2A). In the laser
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control group, the lack of statistical significance for BCVA increase from the last visit before
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surgery at the sixth study visit post-cataract surgery may be attributable to the small number of
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patients in this group. 11
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Overall, 0% and 7.0% of the patients in the laser control and IAI groups, respectively,
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had gained ≥15 letters from baseline at the last study visit before cataract surgery. Following
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cataract surgery, the cumulative incidence for patients who gained ≥15 letters were 35.1% and
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46.6%, respectively (Fig 2B).
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Anatomic Outcomes
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Patients undergoing cataract surgery had a baseline CRT of 441 µm and 486 µm in the laser
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control and IAI groups, respectively (Fig 3A). The corresponding CRT at the last study visit
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before surgery was 342 µm and 301 µm, respectively. At the first study visit post-cataract
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surgery, CRT increased in both groups to 364 µm (difference = 22.5 [95% CI: –22.5, 67.4]; P >
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0.05 compared with last visit before surgery) and 359 µm (difference = 58.0 [95% CI: 13.2,
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102.8]; P = 0.013 compared with last visit before surgery), respectively. By the sixth study visit
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post-cataract surgery, CRT had stabilized to 430 µm (difference = 43.3 [95% CI: –71.3, 157.8];
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P > 0.05 compared with last visit before surgery) and 360 µm (difference = 49.4 [95% CI: 5.1,
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93.7]; P = 0.030 compared with last visit before surgery) in the laser control and IAI groups,
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respectively (Fig 3A).
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Overall, 45.5% and 58.1% of the patients in the laser control and IAI groups,
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respectively, had CRT ≤300 µm on SD-OCT at the last study visit before cataract surgery.
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Subsequently, at the first study visit after cataract surgery, the corresponding cumulative
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incidence for patients with CRT ≤300 µm on SD-OCT were 27.3% and 46.2%, respectively (Fig
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3B).
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Discussion
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This post hoc study revealed that the incidence of cataract surgery did not appear to be
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dependent on treatment group assignment. This finding lends further credence to the notion that
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intravitreal anti-VEGF therapy does not appear to hasten the development of cataracts
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secondary to treatment with intravitreal corticosteroids.
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In patients treated with IAI without any need for rescue treatment with laser and who
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underwent cataract surgery, there was no observed change in BCVA from baseline to the last
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visit before cataract surgery despite achieving normalization of the retina (mean CRT, 301 µm),
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raising the possibility that the lack of BCVA improvement was due to the presence of worsening
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cataracts. While it is possible the lack of vision improvement could have been due to irreversible
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damage to the macula from chronic DME or macular ischemia, it should be noted that, on
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average, patients still experienced an approximate 2-line gain in BCVA following cataract
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surgery. Therefore, it is likely that the cataract was masking vision gains, which were then
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revealed after the cataract was addressed surgically. Furthermore, with continued IAI treatment
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and resultant control of the DME, the initial visual gains post-cataract surgery continued to
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increase, finally stabilizing at approximately the sixth follow-up visit.
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In contrast, while patients in the laser control group without need for rescue treatment
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with IAI also had substantial visual acuity gains as a result of cataract surgery, the initial visual
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gains started to decline around the third study visit post-cataract surgery. A corresponding
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pattern was also seen for the change in CRT over time. This suggests that the visual gains
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achieved following cataract extraction may be compromised without adequate treatment of for
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DME. It should be noted, however, this trend was observed in a relatively small group of
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patients (n = 11) in the analysis, and this exploratory finding should be considered in that
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context.
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These data support results from a post hoc analysis of the ranibizumab RISE and RIDE
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studies, which used similar methodology as the present investigation. In that analysis,
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Moshfeghi et al demonstrated a similar rate of cataract development and time to cataract
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surgery across active treatment and control groups.6 Additionally, like the present study,
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patients gained an average of 2 lines of vision from the last study visit before cataract surgery to
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the first study visit following cataract surgery. This was true of study drug- and control-treated
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eyes.6 That post hoc analysis differed from the present study insofar as only time-domain OCT
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data were available from the RISE and RIDE studies, and the frequency of OCT assessments
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precluded it from being a meaningful metric for post hoc analysis, especially in the second year.
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Nevertheless, the consistency in the average visual acuity gain following cataract surgery using
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a similar in-class agent for the same disease lends support to the findings here.
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A strength of this sub-analysis is that the data derived from two large, prospective,
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active-controlled, randomized, phase 3 clinical trials.5,7 Furthermore, in the IAI groups, a fixed
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dosing algorithm was applied, which leads to a clearer interpretation of the data vis a vis the
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timing of cataract surgery intervention. The necessity for, and timing of, cataract surgery was left
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solely to investigator discretion, which is thus more reflective of the real-world clinical practice
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setting. One major limitation is that this was a post hoc analysis in a relatively small number of
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patients who required cataract surgery during the 2-year follow-up period. An additional
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limitation is the relatively short follow-up period post-cataract surgery, as many of the cataract
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surgeries were performed in the second year of the study. Because of the relatively rigid dosing
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algorithms and variability in timing of cataract surgery due to investigator discretion, we are
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unable to draw meaningful conclusions about the optimal time between an intravitreal anti-
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VEGF injection and cataract surgery. In some respects, this limitation can be viewed as a
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strength, since independent decisions by physicians in a real-world practice setting may be
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similarly free of stringent guidance about the timing of cataract surgery. The fact that there were
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no negative findings and that patients, on average, gained vision despite an initial transient and 14
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modest increase in CRT should reassure physicians (e.g., retinal specialists, cataract surgeons)
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and patients that proceeding with cataract surgery in the setting of actively treated DME is a
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reasonable approach.8
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In conclusion, we observed a similar incidence of cataract surgery for patients in both
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the active treatment and laser control groups. Furthermore, no detrimental effect of cataract
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surgery intervention was found in patients undergoing intravitreal anti-VEGF therapy in this post
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hoc analysis. Rather, following cataract surgery, improved visual acuity was observed despite
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an initial transient and modest increase in macular edema, as measured by SD-OCT imaging.
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Acknowledgments
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Medical writing support was provided by Saba Choudhary, PhD, of Prime Global, New York,
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USA, according to Good Publication Practice guidelines (Link) and funded by Regeneron
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Pharmaceuticals, Inc. All authors had full access to all the data in this study and take complete
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responsibility for the integrity of the data and accuracy of the data analysis.
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Author Contributions:
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Conception and design: Moshfeghi, Thompson, Berliner, Saroj
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Data acquisition and research execution: Moshfeghi, Thompson, Berliner, Saroj
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Data analysis and interpretation: Moshfeghi, Thompson, Berliner, Saroj
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Manuscript preparation and approval: Moshfeghi, Thompson, Berliner, Saroj
16
265
References
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a predictor of macular thickening following cataract surgery in patients with diabetes
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Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal aflibercept for diabetic macular
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edema: 100-week results from the VISTA and VIVID studies. Ophthalmology.
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2015;122:2044-52.
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Steinle NC, Lampen SIR, Wykoff CC. The intersection of diabetes mellitus and cataract surgery: current state of management. Ophthalmology Retina. 2018;2:83-5.
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Figure 1. Kaplan–Meier Analysis Demonstrating Time to First Cataract Surgery in Patients
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Receiving Intravitreal Aflibercept Injection (IAI) or Laser Control.
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CI = confidence interval.
18
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Figure 2. Visual Outcomes Following Cataract Surgery in Patients Receiving Intravitreal
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Aflibercept Injection (IAI) or Laser Control. (A) Line graph representing best-corrected visual
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acuity (BCVA) over time. aP = 0.010, bP < 0.001, and cP = 0.218 compared with last visit before
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surgery. (B) Time to first sustained gain of ≥15 letters from the last visit before surgery.
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ETDRS = Early Treatment Diabetic Retinopathy Study.
295 296
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Figure 3. Anatomic Outcomes Following Cataract Surgery in Patients Receiving Intravitreal
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Aflibercept Injection (IAI) or Laser Control. (A) Line graph representing optical coherence
299
tomography (OCT) central retinal thickness (CRT) over time. aP > 0.05, bP = 0.013, and cP =
300
0.030 compared with last visit before surgery. (B) Kaplan–Meier analysis of the time to first
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sustained (observed at 2 consecutive visits) CRT ≤300 µm on spectral domain-optical
302
coherence tomography (SD-OCT) following cataract surgery in patients receiving IAI or laser
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control.
304 305
20
PRÉCIS Cataract surgery performed in eyes receiving intravitreal aflibercept therapy without need for rescue therapy for diabetic macular edema resulted in visual acuity improvements, despite a transient and mild increase in central retinal thickness.